PROJECT SUMMARY/ABSTRACT The most common alterations of the prostate cancer genome are chromosomal rearrangements that result in aberrant expression of an ETS family transcription factor that is not normally expressed in prostate cells. Expression of these factors, including ERG, ETV1, and ETV4, in prostate cells is oncogenic. However, there are many other ETS factors present in normal prostate that are important for normal functions, and can even be tumor suppressors. Thus, to devise therapies to target ETS factors in prostate cancer, it is critical to understand specific functional mechanisms specific to oncogenic family members. Preliminary data from the applicants' laboratory supports the central hypothesis of this proposal, which proposes that all oncogenic ETS family members activate a similar gene expression program through specific mechanisms that are not used by non-oncogenic ETS proteins. The following three specific aims will be used to identify specific functions of oncogenic ETS proteins: 1) Determine the common transactivation mechanism of ETS factors that drive prostate cancer; 2) Identify mechanisms used by signaling pathways to regulate ERG function in prostate cells; and 3) Determine how oncogenic ETS factors function in prostate cells within the context of the ETS family. These aims are guided by strong preliminary data including the identification of proteins that specifically associate with oncogenic ETS proteins and not with non-oncogenic ETS proteins. In vitro and in vivo assays will test the importance of these interactions, and mechanistic details will be determined using biochemical and genome-wide mapping techniques. Completion of these studies will yield the first understanding of functional mechanisms unique to oncogenic ETS proteins and provide important new molecular targets for pharmacological strategies to prevent both the growth and progression of cancer.